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Genes Chromosomes Cancer. 2015 Nov;54(11):668-80. doi: 10.1002/gcc.22277. Epub 2015 Aug 25.

Detection of chromothripsis-like patterns with a custom array platform for chronic lymphocytic leukemia.

Author information

1
Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
2
Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany.
3
R&D, Department, Quantitative Genomic Medicine Laboratories (qGenomics), Barcelona, Spain.
4
Department of Hematology, Hospital Clínic, IDIBAPS, Barcelona, Spain.
5
Genomics Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
6
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain.
7
Ernest and Helen Scott Haematological Research Institute, Department of Biochemistry, University of Leicester, Leicester, UK.
8
Department of Hematology, Hospital Clínico-IBSAL, Cancer Institute of Salamanca-IBMCC (USAL-CSIC), Salamanca, Spain.

Abstract

Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials.

PMID:
26305789
PMCID:
PMC4832286
DOI:
10.1002/gcc.22277
[Indexed for MEDLINE]
Free PMC Article

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